Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a naturally occurring compound. It is a component of mitochondrial multienzyme complexes which dehydrogenates a-keto acids (e.g. pyruvate). In pathological conditions, lipoic acid is applied in the treatment of diabetic polyneuropathy, liver cirrhosis and metal intoxications. Particularly in diabetic polyneuropathy, the antioxidant activity of lipoic acid is considered to contribute to its therapeutic effect.
The metabolism of lipoic acid has been studied in Pseudomonas (Furr et al., Arch. Biochem. Biophys. 185:576-583 (1978)) and in rats (Spence et al., Arch. Biochem. Biophys. 174:13-19 (1976); Gal et al., Arch. Biochem. Biophys. 89:253-261 (1960); Harrison et al., Arch. Biochem. Biophys. 160:514-522 (1974)). It has been found that in these species lipoic acid is converted by beta oxidation of its pentanoic acid side chain. Regarding the antioxidant activity of lipoic acid, it has been speculated that reduction of lipoic acid to dihydrolipoic acid is an important step in its therapeutic effect. However, no data on the metabolism of lipoic acid in humans is available. Since insight in the kinetics and metabolism of lipoic acid is needed for fully apprehending the pharmacotherapeutic effect, we studied the absorption, metabolism and excretion of lipoic acid.
The lack of knowledge on the pharmacokinetics of lipoic acid is due to the laborious and/or non-specific analytical methods which were available for its detection in biological samples. In the 1960-1970's, only thin layer chromatographic, microbiological and gas chromatographic methods were available. In 1981, HPLC was first applied to the analysis of lipoic acid (Howard et al., J. Chromatogr. 208:129-131 (1981)). This method was suitable for the separation of lipoic acid and several structurally related compounds. However, the UV detection at 330 nm that was applied resulted in a high limit of detection. Later, electrochemical detection (ECD) was used, thus greatly improving the sensitivity of detection in HPLC (Teichert et al., Naunyn-Schmiedeberg's Arch. Pharmacol., Suppl 344:R91 (1991); Kamata et al., J. Pharmaceut. Biomed. Anal. 8:453-456 (1990); Teichert et al., J. Chromatogr. B 672:277-281 (1995)). In this paper we describe an HPLC/ECD method for the detection of lipoic acid and its metabolites in a single run. After oral administration of 1 gram R-lipoic acid to a human volunteer, the plasma concentration of lipoic acid and the metabolites were followed over a 5 hour period. In addition, we elucidated the structure of an unknown metabolite. The pharmacokinetic profile of lipoic acid is discussed in view of its antioxidant activity and its therapeutic application.